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Caloric Restriction preserves replicative potential.....

Magnus Lynch mdl24 at cam.ac.uk
Sun Jan 17 07:47:27 EST 1999

Aubrey de Grey wrote:

> The problem is with your "of course".  Replicative capacity of mouse
> cells in vitro is a lot less than that of human cells, even though their
> telomeres are a lot longer (for Mus musculus) or about the same as ours
> (for Mus spretus).  Similarly, cells from telomerase knockout maintain
> their relicative capacity from one generation to the next despite loss
> of telomere length.  It's certainly possible that this curious uniformity
> of replicative capacity in Mus, irrespective of telomere length, is due
> to all Mus species having the same *minimum* telomere length -- i.e. Mus
> musculus has a bigger variation -- but there is no evidence whatever
> that this minimum telomere length is short enough to trigger replicative
> senescence: thus, rather more likely on present evidence is that mouse
> cells suffer replicative senescence by a mechanism not based on their
> telomere length at all.
> Aubrey de Grey

As I understand it the normal mechanism of replicative senescence in vitro is
that shortening of the telomeres beyond a critical length is detected by the
cell and mitosis is subsequently repressed. This would occur before the
telomeres reached a dangerously short length. If this mechanism is disrupted,
for example by T-antigen from the SV40 virus, then the cell continues to
divide and the telomeres continue to shorten until telomeres are shortened to
such an extent that severe chromosomal abnormalities arise. This stage is
termed "crisis".

Under normal physiological conditions detection of the telomere length is the
only mechanism responsible for replicative senescence, thus absolute telomere
length is irrelevant as the cellular proteins which detect telomere length
can be set for an arbritary minimum length. This explains why mice cells with
widely varying telomere lengths still have a similar replicative capacity.

I have thought of a reason why cells of telomerase knock-out mice retain
their replicative capacity from one generation to the next. As far as I know
there is no experimental evidence for my idea, but I would be interested to
hear any evidence in support or contradiction of it: Is possible that the
length of the telomeres is detected at the beginning of development by some
as yet unidentified mechanism and then 'remembered' by the cell throughout
the lifetime of the animal. The cell would then enter replicative senesence
when the telomeres had shortened by a specific amount. It is clear that if
this mechanism is correct than absolute telomere length would be irrelevant
and although the telomeres of telomerase knock out mice shortened by an
absolute amount every generation the cell would still enter senescence after
the same time.

Magnus Lynch

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